1,3,4,4A,5,9B-HEXAHYDRO-5-PHENYL-2H-INDENO{8 1,2-c{9 -PYRIDINES

ABSTRACT

D R A W I N G

ilnited States Patent [7 2] inventors Anton Ebnother 2 Barenbrunnenweg,4144 Arleshelm; Jean-Michel Bastian, 5 Rhelnparkstrasse, 4127Birslelden; Fulvio Gadlent, 45 Baselerstrasse, 4127 Birsielden, all 01Switzerland [2]] Appl. No. 33,499 [22] Filed Apr. 30, 1970 [45] Patented1971 A [73} Assignee Sandoz Ltd.

, Basee, Switzerland [32] Priorities May 6, 1969 [33] Switzerland [31]6913/69;

June 9, 1969, Switzerland, No. 8747/69; Dec. 11, 1969, Switzerland, No.18423/69; Feb. 5, 1970, Switzerland, No. 1650/70 [54]1,3,4,4A,5,9B-HEXAHYDRO-S-PHENYL-ZH- lNDENO[1,2-C]-PYRIDINES 19 Claims,No Drawings 424/267 [51] int. Cl. C07d 39/00 [50] Field of Search260/293.4

[56] References Cited I UNITED STATES PATENTS 3,408,353 10/1968 Juckeret a1. 260/293 7 3,462,443 8/1969 Paragamian 260/294 3,497,517 2/1970Jucker et al. 260/293 3,499,895 3/1970 .lucker et a1. 260/247.53,513,168 5/1970 Jucker et a1. 260/290 3,573,316 3/1971 Ebnother et a1.260/294.7

Primary Examiner-Henry R. J iles Assistant Examiner-G. Thomas ToddAttorneys-Gerald D. Sharkin, Robert S. Honor, Frederick H.

Weinfeldt, Richard E. Vila and Walter F Jewell ABSTRACT: The inventionconcerns new (4aRS,5SR,9bSR)-,

and (4aRS ,5 RS ,9bRS)-l ,3 ,4,4a,5 ,9bhexahydro-5-phenyl-2l-l-indeno[l,2-c]pyn'dines of the l ,3,4,4A,5,9B-l'lEXAHYDRO-5-PHENYL-2H-HQDENOI l,2- C ]-PYRIDINES IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS Thepresent invention relates to new (4aRS,5SR,9bSR)-, (4aRS,5SR,9bRS)- and(4aRS,5RS,9bRS)- l ,3,4,4a,5,9b-hexahydro-5-phenyl-2H-indeno[1,2-c1pyridines of formula I,

in which R signifies hydrogen, a lower alkyl radical, fluorine,

bromine or chlorine, and each of R, R and R signifies hydrogen, a loweralkyl radical,

fluorine, bromine, chlorine, a lower alkoxy, a lower alkylthio or thetrifluoromethyl radical, and to a process for the production thereof.

Compounds of formula I have the fundamental structure represented byfonnula lX.

The compounds I have three centers of asymmetry in the tricyclic ringsystem, i.e. the carbon atoms in positions 4a, 5 and 9b. Therefore,theoretically there may exist four isomers, which differ from each otherby the position of the hydrogen atoms at the centers of asymmetry.

The nomenclature of R. S. Cahn, C. K. lngold and V. Prelog, AngewandteChemie 78, 413 1966), is used.

Name Position of the hydrogen atoms (4aRS,5SR,9bSR) 4a/9b trans 4a/5trans (MRSJSRBbRS) 40/9! cis 441/5 trans (MRSJRSfibRS) 4a/9b cis 4a/5cis According to the invention the new indenopyridine derivatives offormula I are obtained by reacting a compound of formula ll,

III

in which R, and R have the above significance, and X signifies the acidradical of a reactive ester,

in a solvent which is inert under the reaction conditions and in thepresence of a basic condensation agent.

When the put-pow of the invention is effected using one isomeric form ofa compound of formula II as starting material, then the same isomericform of a compound of formula I is obtained.

The invention is explained in detail below:

A compound of formula ll in a solvent which is inert under the reactionconditions, e.g. in a di(lower)alkyl-carboxylic acid amide such asdimethyl formamide, or in a lower alcohol such as ethanol, or in achlorinated hydrocarbon such as chloroform, or in a ketone such asacetone, is reacted with a compound of formula III, preferably at anelevated temperature between 60 and C., in the presence of a basiccondensation agent, the reaction having a duration of from onehalf to 24hours, but normally 1 to 4 hours. Examples of suitable basiccondensation agents are: alkali metal carbonates such as sodium orpotassium carbonate, or lower tertiary alkyl amines such as triethylamine, or an excess of an equivalent of the compound of fonnula II.

The lower alkyl radicals represented by the symbol R preferably have oneto four, especially one to two carbon atoms, the lower alkyl, alkoxy andalkylthio radicals represented by the symbols R,, R, and R preferablyhave one to four, especially one to two carbon atoms.

One process for the production of the compounds of formula ll ischaracterized in that a compound of formula Ila.

nifies the methyl or benzyl radical, is reacted with an ester ofchloroformic acid offormula, 7

in which R, signifies a lower alkyl radical, a phenyl or benzyl radical,to give the corresponding urethane, and these urethanes are subsequentlyhydrolyzed.

The reaction of a compound of formula lla with a chloroformic acid esterof formula [V is preferably effected in a solvent which is inert underthe reaction conditions, e.g. anhydrous benzene, and at the boilingtemperature of the reaction mixtire. For this reaction chloroformic acidesters of formula lVa,

in which R, signifies a lower alkyl radical, are especially preferred asstarting materials. The resulting urethanes may either be purified inmanner known per se, or used as such for the subsequent urethanesplitting.

The removal of the COOR, radical from the urethanes may be effected withan acid, e.g. a mineral acid such as hydrochlo- .l'iC acid, or a base,e.g. an alkali metal hydroxide such as potassium or sodium hydroxide, ina lower alcohol such as n-buitanol, preferably at the boilingtemperature of the reaction mixture. Hydrolysis with an alkali metalhydroxide may result in a total or partial rearrangement of the(4aRS,5RS,9bRS) compounds into (4ARS,5SR,9bRS) compounds.

in which R, R, and R, have the above significance, or b. cyclizing acompound of formula Va,

3.1- I H OH I Q R1 Va in which R, and R, have the above significance, ito produce a compound of formula lib, 5

- i Nm in which R, and R, have the above significance, or 1 c. reducinga compound of formula IV,

, l N- i i 1 VIZ 1 in which R,, R, and R, have the above significance,

to produce a (4aRS,SRS,9bRS) compound of formula lla, or i d. heating a(4aRS,5RS,9bRS) compound of formula [la in alkaline medium to produce a(4aRS,SSR,9bRS) compound; of formula Ila Processes (a) and (b) mainlyyield (4aRS,5S R,9bS R and (4aRS,5SR,9bRS) compounds, the relationshipof the isome being dependent on the nature of the substituents R, and R,

The cyclization in accordance with processes a and b may be effectedwith polyphosphoric acid, optionally in the. presence of a solvent whichinert under the reaction condi tions, e.g. a cyclic hydrocarbon such asbenzene, toluene, xylene or tetralin, for a period of between l and 24hours at a, temperature between and C.

A process used for the production of compounds of formula V i atae rizsdn h t a nm p i s t qt aalaii ao in which R, and R have the abovesignificance,

VII

is gactedwith an organometallic compound of formula Vlll,

or of formula VIIIa,

-CH2-Li VIIIa 1 in which R, has the above significance, and X signifieschlorine or bromine,

in a solvent which is inert under the reaction conditions, and

the resulting complex ishydrolyzed.

For the reaction of compounds of formula Vll with compounds of formulaVlll or Vllla a cyclic or open-chain ether such as diethyl ether ortetrahydrofuran may, for example, be used as solvent which is inertunder the reaction conditions, and the reaction is preferably effectedat a temperature between 20 and 70 C. Benzyl magnesium bromide or benzyllithium may, for example, be used as organometallic compound of formulaVIII or Vllla.

Compounds of formula Vll may be produced by reacting a Z-phenyl-acrylicacid ester appropriately substituted on the phenyl radical with a3-aminopropionic acid ester appropriately substituted on the nitrogenatom, cyclizing the addition product by treatment with a basiccondensation agent,

and hydrolyzing and dec'arboxylating the resulting compound Compounds offormula Va may be obtained by reacting a compound of formula X,

in which R, and X have the above significance, in a solvent which isinert under the reaction conditions, hydrolyzing the reaction productand reducing the resulting compound of formula X1,

l XI

in which R, and R, have the above significance. i ssemsavnaieifi ni l atheir vhamwbsica'ly lUlOM 0l87 tolerable acid addition salts are usefulbecause they possess pharmacological activity in animals. Moreparticularly, the compounds are useful as serotonin-antagonists, asindicated by the serotonin toxicity test in guinea pigs. The dosageadministered will naturally vary depending on the compound employed, themode of administration and the treatment desired. However, satisfactoryresults are obtained in test animals at doses from about 0.5 to aboutmg./kg. of body weight. As indicated by the said serotonin-antagonistproper-. ties, the compounds can be employed in the treatment ofmigraine, the total daily dose for larger mammals being from about 1 toabout 30 mg. Divided dosage forms suitable for oral application containabout 0.3 to about 15 mg. of the compound admixed with a solid or liquidcarrier or diluent.

The compounds are furthermore useful in the treatment of thrombosis asindicated by their properties in inhibiting hematoblast aggregation,this property being illustrated in the ADP-induced hematoblastaggregation test carried out in vitro. Doses administered will naturallyvary depending on the compound employed, the mode of administration andthe treatment desired. However, indicated doses in warm-blooded animalsare between about 0.5 to about 10 mgJkg. body weight. For larger mammalsthe total daily dosage is in the range of from about 10 to about 400mg., and dosage forms for oral application contain from about 3 to about200 mg. of the compound admixed with solid or liquid carrier or diluent.

The compounds of fonnula l or their physiologically tolerable acidaddition salts may be used as medicaments on their own or in the fonn ofappropriate medicinal preparations with pharmacologically inertadjuvants.

Insofar as the production of the starting materials is not described,these are known or may be produced in accordance with known processes orin a manner analogous to the processes described herein or to processesknown per se.

in the following nonlimitative examples all temperatures are indicatedin degrees Centigrade and are uncorrected.

EXAMPLE I A solution of 7.9 g. of phenacyl chloride in 50 cc. ofdimethyl formamide is added dropwise at room temperature to a suspensionof 14.4 g. of (4aRS,5SR,9bSR)-l,3,4,4a,5,9b-

hexahydro-7-methyl-5-p-tolyl-2H-indeno[ l,2-c]pyridine and 10.9 g. ofsodium carbonate in l00 cc. of dimethyl formamide. The reaction mixtureis subsequently heated in an oil bath of 130 for 2 hours, is then cooledto room temperature and poured on 500 g. of ice. The aqueous phase isshaken out thrice with 500 cc. amounts of diethyl ether, the ether phaseis washed with water, dried over magnesium sulfate, purified with animalcharcoal and concentrated to a volume of about 200 cc. at reducedpressure. After cooling in a refrigerator the title compoundcrystallizes. m.p. 85-86.

The following compounds of formula I may be obtained in a manneranalogous to that described in example 1 (examples 2 to [7):

EXAMPLE l8 8.5 g. of anhydrous sodium carbonate are added to a solutionof 10.0 g. of (4aRS,5SR,9bSR)-l,3,4,4a,5,9b-hexahydro-5-phenyl-2H-indeno[ l ,2-c]pyridine in cc. of N,N-dimethyl formamide,and the mixture is heated to l2.4 g. of phenacyl chloride are addedportionwise at the same temperature during the course of 2 hours, thereaction mixture is stirred at the same temperature for a further 30minutes, is cooled to 20 and is poured into 200 cc. of a 20 percentcommon salt solution. The precipitated product is extracted withmethylene chloride, the organic solution is washed with water, driedover sodium sulfate and the solvent is removed by distillation atreduced pressure. The oily residue is then dissolved in 100 cc. ofethanol, the pH value of the resulting solution is ad- .justed to 3 withhydrochloric acid in ethanol, and 10 cc. of ether are added. The mixtureis allowed to stand at 0, whereupon the precipitated hydrochloride ofthe title compound, haying a m.p. of 250-2 5 5 is filtered off.

This hydrochloride is suspended in 100 cc. of water and 300 cc. ofmethylene chloride, the suspension is made alkaline with a caustic sodasolution, the organic phase is separated and the aqueous phase is againshaken out twice with methylene chloride. The combined extracts arewashed with water, dried over sodium sulfate and the solvent is removedby evaporation at reduced pressure. The residue is crystallizedahydro-Z-phenacyl-S-phenyl-ZH-indeno[ l,2-c]pyridine, having a m.p. ofl03.3-105: i .s obtained. F U m The compounds used as starting materialsmay be obtained as follows:

EXAMPLE l9 (4aRS,5 SR,9bSR l ,3,4,4a,5,9b-hexahydro-7-methyl-5-ptolyl-2H-indenol l ,2-clpyridine (for examplel A solution of 28 g. of chloroforrnic acid ethyl ester in 40 cc. ofbenzene is added dropwise at room temperature during the course of 10minutes to a solution of 19 g. of (4aRS,5SR,9 bSR l ,3,4,4a,5,9b-hexahydro-2,7-dimethyl-5-p-tolyl-2H-indeno[ l,2-c]pyridine incc. of benzene. The reaction mixture is then heated at reflux for 3hours, is subsequently cooled to 20 washed with 2 N hydrochloric acidand with water and dried over sodium sulfate. After removing the solventby distil- ;lation at reduced pressure, the residue is dissolved in l50cc. of n-butanol, 73 g. of potassium hydroxide are added and the mixtureis stirred in an oil bath of 130 for l zfihours. After cooling to 70 themixture is diluted with 300 cc. of benzene Configuration Phys. chem.constants g mmmnmmmmm a: cum mmmmmmmrmmmm 4aRS, 5BR, QbSR-.. M.P.95-100".

4e38, 6BR, QbRS... M.P. of the hydrogen fumarate 190491". 4aRS, 58R,9bSR M.P. 138-139".

4aRS, 5BR, ObSR... M.P. 147-148.

MRS, 5BR, ObSR... M.P. 128-129".

MRS, 5BR, QbSR-.. M.P. 106407".

4sRS, 58R, 9bSR M.P. 121-123".

aRS, 58R, QbSR... M.P. 127-120".

aRS, 58R, DbSR-.. M.P. 112-114.

4aRS, 55R, QbSR... M.P. 108-110".

4aRS, 5R8, QbRS... M.P. of the hydrochloride 237240 (decom.). 4e38, 5BR,9bRS comp.). aRS, 58R, 9bRS... M.P. of the hydrogen fumarate 4aRS,5SR,9bRS M.P. of the hydrogen comp.). 4aRB, 5SR,9bRS M.P. of thehydrogen fumarate 192194 (deoomp. 4-0CH 4aRB,5SR,9bRS M.P. of) thehydrogen furnarate 210212 (de- M.P. of the hydrogen lumarate 193-196"(de- (decom fumarate 197202 81ocomp.

- (4aRS,5RS,9bRS)-1,3,4,

and washed with water until neutral. After drying over mag,- nesiumsulfate the solvent is removed by distillation, whereby the titlecompound distils over at l94/0.01 mm. of Hg. The compound obtained incrystalline form from ethanol/water (6:4) has a m.p. of45-46.

The following compounds of formula 11 may be obtained in a manneranalogous tothat described in example 19 (examples 20 to 23):

EXAMPLE 28- (4aRS,5RS,9bRS )-1 ,3,4,4a,5,9b-hexahydro-2-methyl-5-phenyl-2l-l-indeno{ l,2-c]pyridine (for examples 24 and 29) a solutionof 30 g. of l,3,4,9b-tetrahydro-2-methyl-5-phenyl-2-indeno[l,2-c]pyridine in 200 cc. ofglacial acetic acid is i elsssatslli ea fil how with? rlst s Oxidecatalyst and R2 Configuration Phys. chem. constants For Ex.

4-01 4aRS, 58R, QbSR... B.P. 210 /1106 mm. of Hg 2. 4Cl 4aRS, 68R,SbRS... B.P. 175l80/0.01 mm. of Hg 3, 15, 16, 17. 4-011; 4aRS, 5SR, 9bRSM.P. of the hydrogen iumarate 210213 14. H 4aRS, 5SR, QbSR... M.P. ofthe hydrochloride 292-29 4-11 and 18.

EXAMPLE 2 hydrogen at an initial pressure of 6 atmospheres. The catalyst(4aRS,5RS9bRS)-l ,3 ,4,4a,5,9b-hexahydro-5-phenyl-2H- indeno[ l ,2-c]pyridine (for example 12) A solution of 12 g. of(4aRS,5RS,9bRS)-l,3,4,4a,5,9b-hexahydro-2-methyl-5-phenyl-2-indeno[ l,2-c1pyridine in 120 cc. of absolute benzene is added dropwise at 70--75during the course of half an hour to a solution of 15 g. ofchloroforrnic acid ethyl ester in 60 cc. of benzene. The mixture is thenboiled at reflux for 2%hours, is cooled, some precipitated5,9b-hexahydro-2-methyl-5- phenyl-ZH-indenoI l ,2-clpyridinehydrochloride is filtered off and the filtrate is concentrated byevaporation. The resulting oily, crude(4aRS,5RS,9bRS)-2-ethoxycarbonyl-l,3,4,4a,5,9;b-hcxahydro-2-mcthyl-5-phenyl-2l-l-indeno[ 1 ,2-c]pyridine is boiled atreflux for 16 hours with a mixture of 75 cc. of glacial acetic acid and75 cc. of concentrated hydrochloric acid. The mixture is evaporated todryness in a vacuum, the residue is dissolved in a small amount ofisopropanol and ether is added, whereupon the hydrochloride of(4aRS,5RS,9 bRS)- 1 ,3,4,4a,5 ,9bc-hexahydro5-phenyl-2l-l-indeno[ 1 ,2-c]pyridine crystallizes. it is recrystallized from isopropanol/ethcr andthen has a m.p. of 230-232 (decomp.).

The following compound of formula 11 may be obtained in a manneranalogous to that described in example 24 (example 25):

is then filtered off, the solution is concentrated by evaporation in avacuum, the residue is divided between a dilute caustic soda solutionand methylene chloride, the methylene chloride solution is dried overmagnesium sulfate and concentrated by evaporation. The resulting base isdissolved in isopropanol and a solution of hydrogen chloride in ether isadded, whereupon (4aRS,5 RS,9bRS )-1 ,3 ,4 ,4a,5,9b-hexahydro-2-methyl-5-phenyl-2l-l-indeno[1,2-c1pyridine hydrochloridecrystallizes. After recrystallization from isopropanol the compound hasa m.p. of 270-272+ (decomp.

EXAMPLE 29 (4aRS,5SR,9bRS)-l,3,4,4a,5,9b-hexahydro-2-methyl-5-phenyl-ZH-indenol l,2-c]pyridine (for example 25) Exam- For ple R1 R2Configuration Phys. chem. constants Ex. 25.-." H H 4sRS, ESR, QbRS...M.P. of the hydrochloride 287289 (dec.) 13

EXAMPLE 26 (4aRS,5RS,9bSR)- l ,3,4,4a.5,9b-hexadro-2,7-dimethyl-5-ptolyl-2Hindeno[ l ,2-c]pyridine (for example19) deno[ 1,2-c1pyridine distils over at 165-l70/0.l mm. of H Thecompound obtained in crystalline form from acetonitrilc' has a m.p. of106-l07.

The following compound of formula lla may be obtained in yl-2l-l-indeno[l,2-c]pyridine hydrochloride crystallizes. After crystallization fromisopropanol the compound has a m.p. of 287289 (decomp.

EXAMPLE 3O (4aRS,5SR,9bSR)-7-chloro-5 -p-chlorophenyl-l ,3,4,4a,5,9b-

hexahydro-Z-methyl-ZH-indeno[ l ,2-c1pyridine (for example i g. of4-(p-chloro-a-hydroxybenzyl)-3-p-chlorophenyll-methyl-piperidine areadded portionwise within 15 minutes to 800 g. of polyphosphoric acidpreheated to The reaction mixture is then stirred at the sametemperature for 8 hours and is subsequently poured on a mixture of 3 kg.of ice and 1,500 cc. of methylene chloride while stirring. The mixtureis subsequently made neutral with a concentrated caustic soda solution,the organic phase is separated and the aqueous phase is shaken outthrice with 1,000 cc. amounts of methylene chloride. The organicextracts are washed with a manner analogous to that described in example26 (example 70 water, dried over yfpw y and the V V F -Fn r? m by MRS,53R, llbSR M.P. 83

I distillation at reduced pressure. The oily residue is distilled in ahigh vacuum, whereby the primary fraction distils over as an oil atl95-200/0.0l mm. of Hg. The portion obtained in crystalline form fromacetonitrile is a mixture of isomers having a m.p. of 95-l A fumarate,having a m.p. of 224225 is obtained from this mixture with fumaric acidin ethanol. This salt is divided between diethyl ether and a 2 N causticsoda solution, the ether phase is dried over magnesium sulfate and thesolvent is removed, whereby (4aRS,5SR,9bSR)-7- chloro-S-p-chlorophenyll,3 ,4,4a,5 ,9b-hexahydro-2-methyl- 2H-indeno[ l,2-c]pyridine isobtained. After recrystallization from n-hexane the compound has a m.p.of l l2-l 14.

EXAMPLE 31 l 5 (4aRS,5SR,9bRS )-7-chloro-5-p-chlorophenyll ,3,4,4a,5,9bhexahydro-2H-indeno[ l,2-c]pyridine (for example 21 The process iseffected as described in example 30. After separating the fumarate, themother liquor of the fumarate is completely concentrated by evaporationat reduced pressure and the residue is divided between diethyl ether anda 2 N caustic soda solution. After drying and concentrating the etherphase, the residue is recrystallized from n-hexane, whereby(4aRS,5SR,9bRS)-7-chloro-S-p-chlorophenyll ,3 ,4,4a,5,9b-hexahydro-2-methyl-2H-indenol l ,2-c ]pyridine, having a m.p. ofl22l25, is obtained.

EXAMPLE 32 (4aRS,5SR,9bRS l ,3 ,4,4a,5 ,9b-hexahydro-2,7 iimethyl-5-p-tolyl-2l-l-indeno[ l ,2-c ]pyridine (for example 22) EXAMPLE 334-(a-hydroxy-p-methylbenzyl l -methyl-3-p-tolyl-piperidine (for example26) a. 7.3 g. of magnesium are covered with a layer of absolutetetrahydrofuran, and a few crystals of iodine are added. A solution of51.3 g. of p-bromotoluene in 100 cc. of absolute tetrahydrofuran is thenadded dropwise at such a rate that the reaction is kept going. Thereaction mixture is then heated at reflux for 1% hours, and a solutionof 16.9 g. of l,2,3,6- tetrahydro-l-methyl-isonicotinic acid ethyl esterin 50 cc. of 7 absolute tetrahydrofuran is added to the resultingGrignard solution at reflux temperature. The reaction mixture issubsequently heated at reflux for one hour and 15 minutes, is thencooled to 10 and added with stirring to a mixture of 40 g. of ammoniumchloride, 50 cc. of water, 50 g. of ice and 500 cc. of methylenechloride. After separating the organic phase, the aqueous phase is againshaken out thrice with 300 cc. of 65 methylene chloride, the combinedextracts are dried over magnesium sulfate and the solvent is removed bydistillation. The oily residue is distilled in a high vacuum, wherebyl-. methyl-4-p-toluoyl-3-p-tolyl-piperidine distils over at 205-'2l0/0.05 mm. of Hg. The compound obtained in crystalline form fromdiethyl ether/pentane has a m.p. of l07l08.

b. A solution of 28.5 g. of sodium borohydride in 100 cc. of water,stabilized with 6 cc. of a 5 N caustic soda solution, is added dropwiseto a mlution of 92.l g. of l-methyll-ptoluoyl-3-p-tolyl-piperidine in600 cc. of etha ioljyitltirrgg minutes, at such a rate that the internaltemperature does not exceed 40. The reaction mixture is then stirred at70 for Slhours, is subsequently evaporated to dryness at reducedpressure, and the residue is divided between 300 cc. of water and 300cc. of chloroform. The organic phase is separated and the aqueous phaseis again extracted twice with cc. amounts of chloroform. The combinedextracts are dried over magnesium sulfate, the solvent is removed bydistillation at reduced pressure, and the residue, is. 4-(a-hydroxy-p-methylbenzyl)-l-methyl-3-p-tolyl-piperdine, isrecrystallized from diethyl ether/pentane. m.p. l20-l 23.

The following compounds of formula Va may be produced in a manneranalogous to that described in example 33 (examples 34 and 35):

EXAMPLE 34 (for example 30 and 31) a. 4-p-chlorobenzoyl-3-p-chlorophenyl- 1 -methylpiperidine,m.p. ll8-l20.

b. 4-(a-hydroxy-p-chlorobenzoyl-3-p chlorophenyll methyl-piperdine, m.p.1 42.

EXAMPLE 35 (for example 27) 4-benzoyl-l-methyl-3-phenyl-piperidine, tap.

' /0.05 mm. of Hg.

b. 4-(a-hydroxybenzyl)-l-methyl-3-phenyl-piperidine, rn.p. l53-l 57.

EXAMPLE 36 (4-aRS,5RS,9bRS l ,3,4,4a,5 ,9b-hexahydro-2,7-dimethyl-5-p-tolyl-2H-indeno[ l,2-c]pyridine (for example 3 2) a. A solution of 42g. of 4-bromotoluene in 350 cc. of absolute diethyl ether is addeddropwise within 10 minutes in an atmosphere of nitrogen to 3.5 g. oflithium wire cut in small pieces in 350 cc. of absolute diethyl ether.The mixture is subsequently heated at reflux for lihours, is then cooledto --70 and a solution of 26.9 g. of l,3,4,9b-tetrahydro-2,7-dimethyl-2l-l-indeno[l,2-c]pyridin-5(4aH)-one in 250 cc. of absolute diethylether is added within 30 minutes. Theinternal temperature of thesolution is allowed to rise to 0, stirring is continued at thistemperature for 4 hours, and the reaction mixture is poured on 1,500 g.of ice and 1,500 g. of water, the aqueous phase is extracted with 6,000cc. of chloroform, the extract is dried over magnesium sulfate and isalmost completely concentrated by evaporation at reduced pressure.

deno[l,2-c]pyridinol crystallizes from chloroform diethyl ether. m.p. 2l02l2.

b. 30.7 g. of l,3,4,4a,5,9b-hexahydro-2,7-dimethyl-5-ptolyl-5(2H)-indeno[l,2-c]pyridinol are heated at reflux for 2 hours in200 cc. of 2.5 N hydrochloric acid in methanol. The solution is thencompletely concentrated by evaporation at reduced pressure.l,3,4,9b-tetrahydro-2,7-dimethyl-5-p-tolyl- 2-indeno[l,2-c]pyridinehydrochloride, having a m.p. of 243245 (decomp. is obtained fromalcohol/diethyl ether.

The free base is obtained by dividing the hydrochloride between a 2 Ncaustic soda solution and chloroform, drying the chloroform extract overmagnesium sulfate and concentrating at reduced pressure to,a lightyellow oil.

c. A solution of 26.4 g. of l,3,4,9b-tetrahydro-2,7-dimethyl-5-p-tolyl-2H-indeno[ l,2-c]pyridine in 200 cc. of glacial acetic acid ishydrogenated with 0.6 g. of platinum oxide at 40 and 4 atmospheres for42 hours. After reduction is complete, the catalyst is filtered off andthe filtrate is completely concentrated by evaporation at reducedpressure. The residue is :talren up in 300 cc. of water, is madealkaline with dilute :caustic soda solution and shaken out thrice with200 cc. amounts of diethyl ether. The combined ether extracts are washedwith water until neutral, are dried over magnesium sulfate and thesolvent is comiplaely removed by distillation.

The oily residue is then converted into the hydrochloride with thecalculated amount of hydrochloric acid in ethanol. m.p. 2 2 s sameEXAMPLE 3 7 (4aRS,5SR,9bSR)-1,3 ,4,4a,5 ,9bhexahydro-2-methyl-5-phenyl-2l-l-indenoI 1 ,2-c ]pyridine (for example 23) 2. The compound ofclaim i. which is (4aRS,5SR,9bSR)- 1 ,3 ,4-,4a,5,9b-hexahydro-7-methy1-2- a. 4-benzy1-l-methy1-3-pheny1-piperidinol-4.15.6 g. of magnesium are covered with a layer of 120 cc. of absoluteether, a crystal of iodine and'about 5 cc. of a solution of 81.4 g. ofbenzyl bromidein 400 cc. of absolute other are added, and the mixture isheated until the reaction commences. The remainder of the above benzylbromide solution is then added dropwise at such a rate that the solutionboils continuously, and the solution is subsequently heated at reflux!for a further 4 hours. A solution of 61.6 g. of 1-methyl-3-phen-'y1-piperidone-4 in 300 cc. of absolute ether is added dropwise at tothis benzyl magnesium bromide solution while stirring well, the reactionmixture is stirred at room temperature for a further 3 hours and is thenallowed to stand at room tem-f perature over night. The reaction mixtureis then poured with stirring into a solution of 240g. of ammoniumchloride in 1,500 cc. of ice water, the entire material is filteredthrough, diatomaceous earth, the organic phase is separated and theaqueous solution is again shaken out with ether. The com-. bined ethersolutions are washed with water, dried over potassium carbonate andconcentrated by evaporation at reduced. pressure. The residue iscrystallized from n-hexane and yields4-benzy1'l-methy13-phenyl-piperidinol-4, having a m.p. of 102-l04. b.(4aRS,5SR,9bSR)-1,3,4,4a,5,9lrhexahydro-2-methy1-5- pheny1-2-indeno[ 1,2-c lpyridine.

A mixture of 200 g. of polyphosphoric acidand 200 cc. of xylene ispreheated to 130, and a solution of 19 g. of 4-benzyl-1-methy1-3-phenyl-piperidinol-4 in 40 cc. of xylene is addedwithin 30 minutes while stirring vigorously. The reac-S tion mixture isstirred at 130 for 10 minutes, is cooled to 90 and poured on 600 cc. ofice water. The organic phase is separated, the aqueous portion is washedonce with ether and is then saturated with potassium carbonate. Thebasic aqueous suspension is extracted with methylene chloride, theextract is washed with water and dried over potassium carbonate,whereupon the solvent is removed by evaporation at reduced, pressure.The residue is distilled in a high vacuum, wherebyi (4aRS,5S1R,9bSR)- 1,3,4,4a,5,9b-hexahydro-2-methyl-5-phenyl-2H-indeno[ 1,2-c1pyridinedistils over as an oil at 150 155/O.3 mm. of Hg. m.p. 82-83 from hexane.

What is claimed is:

l. A (4aRS,5S R,9bSR)-, (4aRS,5SR,9bRS or (4aRS,5R;S,9bRS)-1,3,4,4a,5,9b-hexahydro-5-phenyl-2l-l-indeno[ 1,2- c]pyridine ofthe formula:

wherein R is hydrogen, lower alkyl, fluorine, bromine or chlorineend ash9? a- Ra an Metastases-lawman 4. The compound of claim 1 which is 3. Thecompound of claim 1 which is (4aRS,5SR,9bSR)-7-chloro-5-p-chlorophenyl-1 ,3,4,4a,5 ,9b hexahydro-Z-phenacyl-ZH-indeno[ 1,2-

(4aRS,5SR,9bRS)-7-chloro-5-p-chloropheny1- l ,3,4,4a,5,9h-hexahydro-Z-phenacyl-2H-indeno1 1 ,2- .Eh 5. The compound ofclaim .1 which is (4aRS,5SR,9bSR)-2-( 4bromophenacy1)- 1 ,3,4,4a,5 ,9b-

he tahydro-S-pheny1-21-l-indeno[ 1,2-c]pyridine. 6. The compound ofclaim 1 which is (4aRS,5SR,9bSR)-2-(4-chlorophenacy1)-1,3,4,4a,5 ,9b-

hexahydro-S-pheny1-2H-indeno[ 1,2-c1pyridine.

The compound of claim 1 which is (4aRS,$SR,9bSR)- l ,3 ,4 ,4a,5,9b-2-(2,5 -dich1orophenacy11,3,4,4a,5,9h-hexahydro-S-phenyl-21-1-indeno[ 1 ,2-

Q. The compound of claim 1 which is (4aRS,5SR,9bSR)- 1 ,3,4,4a,5,9-hexahydro-2-( 2-methy1- P hr nsesql13 :9!Pyridi V 9. Thecompound of claim l which is Mali-15,5 SR,9bSR)- 1 ,3 ,4,4a,5 ,9b-2-(4-methy1-phenacy1-5- s w -w n rs lfiflrxi iae.

1 1. The compound of claim 1 which is(4aRS,5SR,9bSR)-1,3,4,4a,5,9b-hexahydro-2-(3-methylphenacyD-S-phenyl-l,3,4,4 a, 5, 9 1-1-indeno[ 1 ,2-c ]pyridine. Q

12.The compound of claim 1 which is phenacyl)-5-pheny1-21-1-indeno[1,2-c]pyridine.

13. The compound of claim 1 which is (4aRS,5RS,9bRS l ,3 ,4,4a,5,9b-hexahydro-Z-phenacyl-S- phenyl-2-indeno[ 1,2-clpyridine. V

MQThe compound of claim 1 which is (4aRS5SR,9bRS )-1 ,3,4,4a,5,9b-hexahydro-Z-phenacyl-S- pheny1-21-l-indeno[ l ,2-c ]pyridine.

15. The compound of claim 1 which is (4aRS,5 SR,9bRS )-1 ,3,4,4a,5,9b-hexahydro-7-methy1-2- phenacyl-5-p-tolyl-2l-1-indenoll,2-c]pyridine.

16. The compound of claim 1 which is (4aRS,5 SR,9bRS)-1 ,3 ,4,4a,5,9b-hexahydro-2-p-methoxyphenacyl-ZH-indenoI 1 ,2-c ]pyridine.

117. The compound of claim 1 which is(4aRS,5SR,9blRS)-7-chloro-5-p-ch1orophenyl- 1 ,3,4,4a,5,9b-hexahydro-Z-m-methy1phenacyl-2H-indeno[ 1 ,2-c1pyridine.

18. The compound of claim 1 which is(4aRS,SSR,9bRS)-7-ch1oro5-p-chlorophenyl-2-( 3 ,4-

dimethoxyphenacynl ,3 ,4,4a,5 ,9b-hexhydro-2H-indeno[ 1 ,2-c]pyridine.

119. The compound of claim 1. which is (4aRS,5 SR,9bSlR)- 1 ,3,4,4a,5,9b-hexahydro-2-phenacyl-5- phenacy1-2H-indeno[ l,2c]pyridine.

2. The compound of claim 1 which is(4aRS,5SR,9bSR)-1,3,4,4a,5,9b-hexahydro-7-methyl-2-phenacyl-5-p-tolyl-2H-indeno(1,2-c)pyridine.
 3. The compound of claim 1 which is(4aRS,5SR,9bSR)-7-chloro-5-p-chlorophenyl-1,3,4,4a,5,9b-hexahydrO-2-phenacyl-2H-indeno(1,2-c)pyridine.4. The compound of claim 1 which is(4aRS,5SR,9bRS)-7-chloro-5-p-chlorophenyl-1,3,4,4a,5,9b-hexahydro-2-phenacyl-2H-indeno(1,2-c)pyridine.5. The compound of claim 1 which is(4aRS,5SR,9bSR)-2-(4-bromophenacyl)-1,3,4,4a,5,9b-hexahydro-5-phenyl-2H-indeno(1,2-c)pyridine.
 6. The compound of claim 1 which is(4aRS,5SR,9bSR)-2-(4-chlorophenacyl)-1,3,4,4a,5,9b-hexahydro-5-phenyl-2H-indeno(1,2-c)pyridine.
 7. The compound of claim 1 which is(4aRS,5SR,9bSR)-1,3,4,4a,5,9b-2-(2,5-dichlorophenacyl)-1,3,4,4a,5,9b-hexahydro-5-phenyl-2H-indeno(1,2-c)pyridine.
 8. The compound ofclaim 1 which is(4aRS,5SR,9bSR)-1,3,4,4a,5,9-hexahydro-2-(2-methyl-phenacyl)-5-phenyl-2H-indeno(1,2-c)pyridine.
 9. The compound of claim 1 which is(4aRS,5SR,9bSR)-1,3,4,4a,5,9b-hexahydro-2-(3-methyl-phenacyl)-5-phenyl-2H-indeno(1,2-c)pyridine.
 10. The compound of claim 1 which is(4aRS,5SR,9bSR)-1,3,4,4a,5,9b-2-(4-methyl-phenacyl-5-phenyl-2H-indeno(1,2-c)pyridine.
 11. The compound of claim 1 which is(4aRS,5SR,9bSR)-1,3,4,4a,5,9b-hexahydro-2-(3-methyl-phenacyl)-5-phenyl-1,3,4,4 a, 5, 9 H-indeno(1,2-c)pyridine.
 12. The compound of claim 1which is(4aRS,5SR,9bSR)-1,3,4,4a,5,9b-hexahydro-2-(4-methyl-phenacyl)-5-phenyl-2H-indeno(1,2-c)pyridine.
 13. The compound of claim 1 which is(4aRS,5RS,9bRS)-1,3,4,4a,5,9b-hexahydro-2-phenacyl-5-phenyl-2-indeno(1,2-c)pyridine.
 14. The compound of claim 1 which is(4aRS5SR,9bRS)-1,3,4,4a,5,9b-hexahydro-2-phenacyl-5-phenyl-2H-indeno(1,2-c)pyridine.
 15. The compound of claim 1 which is(4aRS,5SR,9bRS)-1,3,4,4a,5,9b-hexahydro-7-methyl-2-phenacyl-5-p-tolyl-2H-indeno(1,2-c)pyridine.
 16. The compound of claim 1 which is(4aRS,5SR,9bRS)-1,3,4,4a,5,9b-hexahydro-2-p-methoxyphenacyl-2H-indeno(1,2-c)pyridine.
 17. The compound of claim 1 which is(4aRS,5SR,9bRS)-7-chloro-5-p-chlorophenyl-1,3,4,4a,5,9b-hexahydro-2-m-methylphenacyl-2H-indeno(1,2-c)pyridine.
 18. The compound of claim 1which is(4aRS,5SR,9bRS)-7-chloro5-p-chlorophenyl-2-(3,4-dimethoxyphenacyl)-1,3,4,4a,5,9b-hexhydro-2H-indeno(1,2-c)pyridine.
 19. The compound ofclaim 1 which is(4aRS,5SR,9bSR)-1,3,4,4a,5,9b-hexahydro-2-phenacyl-5-phenacyl-2H-indeno(1,2-c)pyridine.